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A proteolytic defect as a cause of aging

Understanding the biology of aging and therapeutic approach to pathologies associated with its development are facilitated by the study of syndromes of accelerated aging or progeria. These syndromes are characterized by early onset of physiological changes normally associated with old age.Progeroid syndromes, Werner’s syndrome or progeria of the adult, are caused by defects in various systems involved in maintaining the integrity of genetic material. By contrast, the progeroid laminopatías are caused by defects in components of the nuclear envelope.

The most widely studied laminopatía progeroid syndrome, Hutchinson-Gilford progeria child or, in its most common form is caused by a mutation in the LMNA gene, which encodes two components of the nuclear lamina, the lamin A and C. Lamin A is synthesized as a precursor called pre-laminated A, which undergoes a series of posttranslational modifications that include prenylation of the carboxyl terminal peptide and subsequent proteolytic removal carried out by the metalloprotease FACE-1/Zmpste24.1 The mutation causing the Hutchinson-Gilford syndrome causes the synthesis of a pre-laminated variant known as progerin, which lacks the cleavage site of FACE-1 and, therefore, remains prenylated constitutively. Similarly, the FACE-1 deficiency leads to accumulation of pre-laminated to prenylated and leads to symptoms similar to those caused by the accumulation of progerin.

The use as a model of mice deficient in Zmpste24 / FACE-1 has shown the role of abnormal activation of the p53 pathway in the development of progeroid phenotype and allowed to establish the causal relationship between the accumulation of prenylated forms of lamin A and develop symptoms of accelerated aging. 2 Furthermore, this work opened the possibility of reversing this phenotype through reduced levels of pre-laminated A prenylated. This same animal model has also recently allowed to identify shifts in the number and functionality of stem cells associated with accelerated aging phenotype. 3